The long term objective of this project is the localization and identification of the gene responsible for familial cold urticaria. Familial cold urticaria is an excellent example of the immune system's response to physical stimuli in the environment. This condition provides a novel opportunity to study underlying mechanisms of inflammation from a molecular genetic perspective because of its classical autosomal dominant inheritance pattern. It is unique to have a large affected family motivated to participate in the proposed research in close proximity to UCSD which has the resources necessary to perform molecular genetic studies. There are many inflammatory diseases induced by physical stimuli and they may share common mechanisms with other inflammatory disorders. Therefore this genetic study of familial cold urticaria will likely increase the understanding of the molecular mechanisms regulating inflammatory responses. Ultimately this will lead to improved treatment of familial cold urticaria and other inflammatory disorders. The specific goals of this project are: (1) to conduct a systematic survey of the entire genome using short tandem repeat polymorphisms with markers spaced at 20 centiMorgans (cM) initially and later at 10 cM if necessary; (2) to perform multi-point linkage analysis using the LINKAGE program to identify regions with a lod score greater than plus 2 and after finer mapping of these regions to identify regions with a lod score greater than plus 3 and an approximate size of 1-2 cM; (3) to develop a contiguous physical map using a combination of cloning systems and techniques such as chromosome walking and STS content mapping; (4) to identify candidate genes within the limited region using techniques such as cDNA selection and exon trapping; and (5) to screen these genes initially for gross rearrangements using pulse field gel electrophoresis and then for more subtle DNA alterations using single strand conformational polymorphism analysis. The achievement of these goals will result in identification of the gene responsible for familial cold urticaria which will ultimately lead to an understanding of the mechanism of the inflammatory response to a physical stimulus.